{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T00:00:59Z","timestamp":1793923259400,"version":"4.8.0"},"reference-count":72,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,9,4]],"date-time":"2024-09-04T00:00:00Z","timestamp":1725408000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001663","name":"Volkswagen Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001663","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Aging Neurosci."],"abstract":"<jats:p>The <jats:italic>amyloid-cascade-hypothesis<\/jats:italic> of the pathogenesis of Alzheimer\u2019s disease (AD) was introduced 32\u2009years ago, in 1992. From early on, this clear and straight forward hypothesis received a lot of attention, but also a lot of substantial criticism. Foremost, there have always been massive doubts that a complex age-associated disorder of the most intricate organ of the human body, the brain, can be explained by a linear, one-dimensional cause-and-effect model. The amyloid-cascade defines the generation, aggregation, and deposition of the amyloid beta peptide as the central pathogenic mechanism in AD, as the ultimate trigger of the disease, and, consequently, as the key pharmacological target. Certainly, the original 1992 version of this hypothesis has been refined by various means, and the \u2018formulating fathers\u2019 followed up with a few reappraisals and partly very open reflections in 2002, 2006, 2009, and 2016. However, up until today, for the supporters of this hypothesis, the central and initial steps of the cascade are believed to be driven by amyloid beta\u2014even if now displayed somewhat more elaborate. In light of the recently published clinical results achieved with anti-amyloid antibodies, the controversy in the field about (1) the clinical meaningfulness of this approach, (2) the significance of clearance of the amyloid beta peptide, and last but not least (3) the relevance of the amyloid-cascade-hypothesis is gaining momentum. This review addresses the interesting manifestation of the amyloid-cascade-hypothesis as well as its ups and downs over the decades.<\/jats:p>","DOI":"10.3389\/fnagi.2024.1459224","type":"journal-article","created":{"date-parts":[[2024,9,4]],"date-time":"2024-09-04T04:47:07Z","timestamp":1725425227000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":51,"title":["In 2024, the amyloid-cascade-hypothesis still remains a working hypothesis, no less but certainly no more"],"prefix":"10.3389","volume":"16","author":[{"given":"Christian","family":"Behl","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,9,4]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","DOI":"10.1101\/2024.05.10.24307165","article-title":"The impact of APOE \u03b54 in Alzheimer's disease: a meta-analysis of voxel-based morphometry studies","author":"Bailey","year":"2024","journal-title":"medRxiv"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"849","DOI":"10.1016\/j.tips.2017.07.002","article-title":"Amyloid in Alzheimer\u2019s disease: guilty beyond reasonable doubt?","volume":"38","author":"Behl","year":"2017","journal-title":"Trends Pharmacol. Sci."},{"key":"ref3","doi-asserted-by":"crossref","DOI":"10.1007\/978-3-031-31570-1","volume-title":"Alzheimer\u2019s disease research: What has guided research so far and why it is high time for a paradigm shift","author":"Behl","year":"2023"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"944","DOI":"10.1016\/0006-291x(92)90837-b","article-title":"Vitamin E protects nerve cells from amyloid beta protein toxicity","volume":"186","author":"Behl","year":"1992","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"817","DOI":"10.1016\/0092-8674(94)90131-7","article-title":"Hydrogen peroxide mediates amyloid beta protein toxicity","volume":"77","author":"Behl","year":"1994","journal-title":"Cell"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"412","DOI":"10.1038\/s41588-022-01024-z","article-title":"New insights into the genetic etiology of Alzheimer\u2019s disease and related dementias","volume":"54","author":"Bellenguez","year":"2022","journal-title":"Nat. Genet."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"536","DOI":"10.3390\/jcm13020536","article-title":"Controversial past, splendid present, unpredictable future: a brief review of Alzheimer disease history","volume":"13","author":"Bermejo-Pareja","year":"2024","journal-title":"J. Clin. Med."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"4757","DOI":"10.1016\/j.cell.2023.09.023","article-title":"Accelerating Alzheimer's therapeutic development: the past and future of clinical trials","volume":"186","author":"Boxer","year":"2023","journal-title":"Cell"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"958","DOI":"10.1038\/s41374-019-0231-z","article-title":"The amyloid cascade and Alzheimer's disease therapeutics: theory versus observation","volume":"99","author":"Castellani","year":"2019","journal-title":"Lab. Investig."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"1491","DOI":"10.1126\/science.1062097","article-title":"Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils","volume":"293","author":"G\u00f6tz","year":"2001","journal-title":"Science"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"102161","DOI":"10.1016\/j.arr.2023.102161","article-title":"Once upon a time, the amyloid cascade hypothesis","volume":"93","author":"Granzotto","year":"2024","journal-title":"Ageing Res. Rev."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"1073","DOI":"10.1016\/S0197-4580(02)00042-8","article-title":"Testing times for the \u201camyloid cascade hypothesis\u201d","volume":"23","author":"Hardy","year":"2002","journal-title":"Neurobiol. Aging"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"151","DOI":"10.3233\/JAD-2006-9S317","article-title":"Alzheimer's disease: the amyloid cascade hypothesis: an update and reappraisal","volume":"9","author":"Hardy","year":"2006","journal-title":"JAD"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"1129","DOI":"10.1111\/j.1471-4159.2009.06181.x","article-title":"The amyloid hypothesis for Alzheimer\u2019s disease: a critical reappraisal","volume":"110","author":"Hardy","year":"2009","journal-title":"J. Neurochem."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"1040","DOI":"10.1111\/febs.14004","article-title":"The discovery of Alzheimer-causing mutations in the APP gene and the formulation of the \u201camyloid cascade hypothesis\u201d","volume":"284","author":"Hardy","year":"2017","journal-title":"FEBS J."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1016\/0165-6147(91)90609-v","article-title":"Amyloid deposition as the central event in the aetiology of Alzheimer's disease","volume":"12","author":"Hardy","year":"1991","journal-title":"Trends Pharmacol. Sci."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1126\/science.1566067","article-title":"Alzheimer's disease: the amyloid Cascade hypothesis","volume":"256","author":"Hardy","year":"1992","journal-title":"Science"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1126\/science.1072994","article-title":"The amyloid hypothesis of Alzheimer's disease: Progress and problems on the road to therapeutics","volume":"297","author":"Hardy","year":"2002","journal-title":"Science"},{"key":"ref0001","doi-asserted-by":"crossref","first-page":"7951","DOI":"10.1523\/JNEUROSCI.20-21-07951.2000","article-title":"Mice with combined gene knock-outs reveal essential and partially redundant functions of amyloid precursor protein family members","volume":"20","author":"Heber","year":"2000","journal-title":"J. Neurosci."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"794","DOI":"10.1038\/nn.4017","article-title":"The case for rejecting the amyloid cascade hypothesis","volume":"18","author":"Herrup","year":"2015","journal-title":"Nat. Neurosci."},{"key":"ref20","doi-asserted-by":"crossref","DOI":"10.7551\/mitpress\/12423.001.0001","volume-title":"How not to study a disease: The story of Alzheimer's","author":"Herrup","year":"2021"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"102173","DOI":"10.1016\/j.arr.2023.102173","article-title":"Revision of Alzheimer's diagnostic criteria or relocation of the Potemkin village","volume":"93","author":"H\u00f8ilund-Carlsen","year":"","journal-title":"Ageing Res. Rev."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"3892","DOI":"10.3390\/ijms25073892","article-title":"Alzheimer's amyloid hypothesis and antibody therapy: melting glaciers?","volume":"25","author":"H\u00f8ilund-Carlsen","year":"","journal-title":"Int. J. Mol. Sci."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"2121","DOI":"10.1038\/s41591-024-02988-7","article-title":"Revised criteria for the diagnosis and staging of Alzheimer's disease","volume":"30","author":"Jack","year":"2024","journal-title":"Nat. Med."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"1401","DOI":"10.3233\/JAD-220569","article-title":"It's groundhog day! What can the history of science say about the crisis in Alzheimer's disease research?","volume":"90","author":"Jacobs","year":"2022","journal-title":"J. Alzheimers Dis."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s00702-021-02449-2","article-title":"Recent update on the heterogeneity of the Alzheimer's disease spectrum","volume":"129","author":"Jellinger","year":"2022","journal-title":"J. Neural Transm. (Vienna)"},{"key":"ref0002","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1038\/325733a0","article-title":"The precursor of Alzheimer\u2019s disease amyloid A4 protein resembles a cell-surface receptor","volume":"325","author":"Kang","year":"1987","journal-title":"Nature"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1001\/archneur.1976.00500040001001","article-title":"The prevalence and malignancy of Alzheimer disease","volume":"33","author":"Katzman","year":"1976","journal-title":"Arch. Neurol."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"497","DOI":"10.3233\/JAD-230099","article-title":"The anti-amyloid monoclonal antibody Lecanemab: 16 cautionary notes","volume":"94","author":"Kepp","year":"2023","journal-title":"J. Alzheimers Dis."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"1124","DOI":"10.1016\/j.bbagen.2009.07.016","article-title":"The unsolved relationship of brain aging and late-onset Alzheimer disease","volume":"1790","author":"Kern","year":"2009","journal-title":"Biochim. Biophys. Acta Gen. Subj."},{"key":"ref29","volume-title":"The structure of scientific revolutions","author":"Kuhn","year":"1970"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"943","DOI":"10.17219\/acem\/171379","article-title":"Lecanemab (Leqembi) is not the right drug for patients with Alzheimer's disease","volume":"32","author":"Kurkinen","year":"2023","journal-title":"Adv. Clin. Exp. Med."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"1446","DOI":"10.1126\/science.1064684","article-title":"Biomedicine. Tauists and beta-aptists united--well almost!","volume":"293","author":"Lee","year":"2001","journal-title":"Science"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"137","DOI":"10.3233\/jad-2004-6205","article-title":"Perspectives on the amyloid-beta cascade hypothesis","volume":"6","author":"Lee","year":"","journal-title":"J. Alzheimers Dis."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1196\/annals.1297.001","article-title":"Challenging the amyloid cascade hypothesis: senile plaques and amyloid-beta as protective adaptations to Alzheimer disease","volume":"1019","author":"Lee","year":"","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"1487","DOI":"10.1126\/science.1058189","article-title":"Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP","volume":"293","author":"Lewis","year":"2001","journal-title":"Science"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"102290","DOI":"10.1016\/j.arr.2024.102290","article-title":"A critical appraisal of blood-based biomarkers for Alzheimer's disease","volume":"96","author":"Lista","year":"2024","journal-title":"Ageing Res. Rev."},{"key":"ref36","doi-asserted-by":"crossref","DOI":"10.23943\/princeton\/9780691149783.001.0001","volume-title":"The Alzheimer conundrum: Entanglements of dementia and aging","author":"Lock","year":"2013"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"316","DOI":"10.1111\/jnc.15593","article-title":"Editorial: Honouring John Hardy - a true pioneer in research","volume":"161","author":"Lourenco","year":"2022","journal-title":"J. Neurochem."},{"key":"ref38","doi-asserted-by":"publisher","first-page":"1304","DOI":"10.1016\/j.neuron.2022.03.004","article-title":"ApoE Cascade hypothesis in the pathogenesis of Alzheimer's disease and related dementias","volume":"110","author":"Martens","year":"2022","journal-title":"Neuron"},{"key":"ref39","article-title":"Cascade","year":"2024"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"846902","DOI":"10.3389\/fnagi.2022.846902","article-title":"Most pathways can be related to the pathogenesis of Alzheimer's disease","volume":"14","author":"Morgan","year":"2022","journal-title":"Front. Aging Neurosci."},{"key":"ref41","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1186\/s40478-014-0135-5","article-title":"Inconsistencies and controversies surrounding the amyloid hypothesis of Alzheimer's disease","volume":"2","author":"Morris","year":"2014","journal-title":"Acta Neuropathol. Commun."},{"key":"ref42","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1016\/s0166-2236(00)02031-2","article-title":"Alzheimer's disease-do tauists and baptists finally shake hands?","volume":"25","author":"Mudher","year":"2002","journal-title":"Trends Neurosci."},{"key":"ref43","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1016\/S0166-2236(97)01168-5","article-title":"Alzheimer's disease: a re-examination of the amyloid hypothesis","volume":"21","author":"Neve","year":"1998","journal-title":"Trends Neurosci."},{"key":"ref44","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1016\/0197-4580(94)90079-5","article-title":"Free radicals, proteolysis, and the degeneration of neurons in Alzheimer disease: how essential is the beta-amyloid link?","volume":"15","author":"Nixon","year":"1994","journal-title":"Neurobiol. Aging"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"1161","DOI":"10.1023\/a:1007675508413","article-title":"The endosomal-lysosomal system of neurons in Alzheimer's disease pathogenesis: a review","volume":"25","author":"Nixon","year":"2000","journal-title":"Neurochem. Res."},{"key":"ref0003","doi-asserted-by":"crossref","first-page":"6990","DOI":"10.1073\/pnas.0500466102","article-title":"Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degeneration in vivo","volume":"102","author":"Noble","year":"2005","journal-title":"AProc. Natl Acad. Sci. USA."},{"key":"ref46","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1038\/s41582-018-0116-6","article-title":"A critical appraisal of amyloid-\u03b2-targeting therapies for Alzheimer disease","volume":"15","author":"Panza","year":"2019","journal-title":"Nat. Rev. Neurol."},{"key":"ref47","doi-asserted-by":"publisher","first-page":"14946","DOI":"10.1523\/JNEUROSCI.4305-10.2010","article-title":"Amyloid-Independent Mechanisms in Alzheimer's Disease Pathogenesis","volume":"30","author":"Pimplikar","year":"2010","journal-title":"J. Neurosci."},{"key":"ref48","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1016\/B978-0-323-85555-6.00019-9","article-title":"Lessons from antiamyloid-\u03b2 immunotherapies in Alzheimer's disease","volume":"193","author":"Plascencia-Villa","year":"2023","journal-title":"Handb. Clin. Neurol."},{"key":"ref49","doi-asserted-by":"publisher","first-page":"623","DOI":"10.1016\/0197-4580(92)90069-a","article-title":"Toxicity of synthetic a beta peptides and modeling of Alzheimer's disease","volume":"13","author":"Price","year":"1992","journal-title":"Neurobiol. Aging"},{"key":"ref50","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1016\/j.trci.2016.09.002","article-title":"Multiple comorbid neuropathologies in the setting of Alzheimer's disease neuropathology and implications for drug development","volume":"3","author":"Rabinovici","year":"2017","journal-title":"Alzheimers Dement (NY)"},{"key":"ref51","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1038\/d41586-023-00030-3","article-title":"FDA approves Alzheimer\u2019s drug lecanemab amid safety concerns","volume":"613","author":"Reardon","year":"2023","journal-title":"Nature"},{"key":"ref52","first-page":"167","article-title":"What do recent clinical trials teach us about the etiology of AD","volume-title":"GeNeDis 2018","author":"Robakis","year":"2020"},{"key":"ref53","doi-asserted-by":"publisher","first-page":"1051","DOI":"10.1016\/S0197-4580(01)00342-6","article-title":"A\u03b2 as a bioflocculant: implications for the amyloid hypothesis of Alzheimer\u2019s disease","volume":"23","author":"Robinson","year":"2002","journal-title":"Neurobiol. Aging"},{"key":"ref54","doi-asserted-by":"publisher","first-page":"1467","DOI":"10.1212\/wnl.43.8.1467","article-title":"Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer's disease","volume":"43","author":"Saunders","year":"1993","journal-title":"Neurology"},{"key":"ref55","doi-asserted-by":"publisher","first-page":"342","DOI":"10.14283\/jpad.2023.73","article-title":"Viewpoint: when it comes to Lecanemab (and Donanemab), how might we think about 'Reasonable and Necessary'?","volume":"10","author":"Schneider","year":"2023","journal-title":"J. Prev Alzheimers Dis."},{"key":"ref56","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1016\/0896-6273(91)90052-2","article-title":"The molecular pathology of Alzheimer's disease","volume":"6","author":"Selkoe","year":"1991","journal-title":"Neuron"},{"key":"ref57","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1038\/s43587-024-00611-5","article-title":"The advent of Alzheimer treatments will change the trajectory of human aging","volume":"4","author":"Selkoe","year":"2024","journal-title":"Nat Aging"},{"key":"ref58","doi-asserted-by":"publisher","first-page":"595","DOI":"10.15252\/emmm.201606210","article-title":"The amyloid hypothesis of Alzheimer's disease at 25 years","volume":"8","author":"Selkoe","year":"2016","journal-title":"EMBO Mol. Med."},{"key":"ref59","doi-asserted-by":"publisher","first-page":"eadk4858","DOI":"10.1126\/science.adk4858","article-title":"A petavoxel fragment of human cerebral cortex reconstructed at nanoscale resolution","volume":"384","author":"Shapson-Coe","year":"2024","journal-title":"Science"},{"key":"ref60","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1001\/jama.2023.13239","article-title":"Donanemab in early symptomatic Alzheimer disease: the TRAILBLAZER-ALZ 2 randomized clinical trial","volume":"330","author":"Sims","year":"2023","journal-title":"JAMA"},{"key":"ref61","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1016\/0306-9877(94)90132-5","article-title":"Alzheimer disease: an imbalance of proteolytic regulation?","volume":"42","author":"Smith","year":"1994","journal-title":"Med. Hypotheses"},{"key":"ref62","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1016\/s0891-0618(98)00061-1","article-title":"What are the facts and artifacts of the pathogenesis and etiology of Alzheimer disease?","volume":"16","author":"Smith","year":"1998","journal-title":"J. Chem. Neuroanat."},{"key":"ref63","doi-asserted-by":"publisher","first-page":"432","DOI":"10.1111\/jnc.14079","article-title":"Re-imagining Alzheimer's disease \u2013 the diminishing importance of amyloid and a glimpse of what lies ahead","volume":"143","author":"Tse","year":"2017","journal-title":"J. Neurochem."},{"key":"ref64","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1056\/NEJMoa2212948","article-title":"Lecanemab in early Alzheimer's disease","volume":"388","author":"van Dyck","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref65","doi-asserted-by":"publisher","first-page":"o3010","DOI":"10.1136\/bmj.o3010","article-title":"Lecanemab for Alzheimer's disease","volume":"379","author":"Walsh","year":"2022","journal-title":"Br. Med. J."},{"key":"ref66","volume-title":"The myth of Alzheimer's: What aren't you being told about today's most dreaded diagnosis","author":"Whitehouse","year":"2008"},{"key":"ref001","doi-asserted-by":"publisher","first-page":"1939","DOI":"10.1111\/jgs.18793.","article-title":"Who gets to decide on what it means to have Alzheimer\u2019s disease?","volume":"72","author":"Widera","year":"2024","journal-title":"J Am Geriatr Soc."},{"key":"ref67","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1126\/science.2474201","article-title":"Neurotoxicity of a fragment of the amyloid precursor associated with Alzheimer's disease","volume":"245","author":"Yankner","year":"1989","journal-title":"Science"},{"key":"ref68","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1126\/science.2218531","article-title":"Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides","volume":"250","author":"Yankner","year":"1990","journal-title":"Science"}],"container-title":["Frontiers in Aging Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnagi.2024.1459224\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,9,4]],"date-time":"2024-09-04T04:47:17Z","timestamp":1725425237000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnagi.2024.1459224\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,4]]},"references-count":72,"alternative-id":["10.3389\/fnagi.2024.1459224"],"URL":"https:\/\/doi.org\/10.3389\/fnagi.2024.1459224","relation":{},"ISSN":["1663-4365"],"issn-type":[{"value":"1663-4365","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,4]]},"article-number":"1459224"}}